Carcinoembyronic antigen-related cell adhesion molecule 6 (CEACAM6) is a glycosylphosphatidylinositol (GPI)-linked protein that we have shown is overexpressed in pancreatic adenocarcinoma and in advanced pancreatic intraepithelial neoplasia (PanIN) lesions. Patients with CEACAM6-positive pancreatic adenocarcinomas have poorer postoperative survival than patients with CEACAM6-negative cancers. Our studies suggest that CEACAM6 promotes: 1) invasiveness, and 2) chemoresistance to gemcitabine (the principal chemotherapeutic agent used for treating patients with advanced pancreatic cancer). These studies also suggest that ribonucleotide reductase M2 subunit (RRM2), itself a downstream target of CEACAM6 signaling, plays a critical role in mediating resistance to gemcitabine. We have shown that targeted therapy directed against either CEACAM6 or RRM2 inhibits tumor progression and attenuates resistance to gemcitabine-induced cytotoxicity in experimental pancreatic cancer. We now propose to characterize downstream effectors of CEACAM6 and RRM2 signaling. Based on our preliminary data, we have formulated three specific aims: 1. To test the hypothesis that CEACAM6 over expression promotes cellular invasive potential through a c-Src- and Akt-dependent mechanism in pancreatic cancer. 2. To test the hypothesis that RRM2 over expression promotes resistance to gemcitabine-induced cytotoxicity through a Raf-1-, protein kinase CK2-, and NF-kB-dependent mechanism in pancreatic cancer. 3. To test the hypothesis that CEACAM6 and RRM2 signaling pathway components are coordinately expressed in pancreatic adenocarcinomas and in PanIN lesions. By characterizing CEACAM6 and RRM2 signaling pathways, we hope to identify: 1) novel therapeutic targets, 2) new prognostic factors, and 3) early detection strategies for pancreatic cancer.